Garlic Metabolism and Cytochrome P450 Modulation

大蒜代谢和细胞色素 P450 调节

基本信息

批准号：
7228080
负责人：
DANNY D SHEN
金额：
$ 20.62万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-06-01 至 2009-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7228080
关键词：
ABCB1 gene Acute Affect Alprazolam American Animals Anticoagulants Area Attention Blood Bupropion CYP2E1 gene CYP3A4 gene Caffeine Case Study Chlorzoxazone Cholesterol Chronic Class Classification Clinical Clinical Research Collection Comparative Study Conflict (Psychology)Cytochrome P450 Daily Data Digoxin Documentation Drug Interactions Drug Kinetics Enzymes Garlic Garlic Extract HIV Protease Inhibitors HIV-1 Health Professional Hepatic Herb Herb-Drug Interactions Herbal Medicine Human Human Volunteers Hydrolysis In Vitro Intake Intestinal Mucosa Intestines Lead Lipids Literature Liver Marketing Measures Membrane Transport Proteins Metabolic Metabolic Biotransformation Metabolism Metoprolol Midazolam Mus Numbers Omeprazole Oral P-Glycoprotein Patients Peptides Personal Satisfaction Pharmaceutical Preparations Phase Plasma Powder dose form Preparation Protease Inhibitor Protein Isoforms Rattus Recombinants Regulation Reporting Research Research Personnel Ritonavir Safety Sampling Saquinavir Sorting - Cell Movement Steam Sulfides Therapeutic Thinking Time Tolbutamide Treatment Protocols Universities Urine Variant Warfarin Washington absorption aged allicin allyl sulfide clinically significant cytochrome P450 3A design follow-up healthy volunteer human CYP2C9 protein human study human subject in vivo metabolic abnormality assessment programs treatment duration

项目摘要

DESCRIPTION (provided by applicant): Garlic supplements are widely used for the treatment of high blood cholesterol and lipids. Until recently, garlic supplements were thought to be well tolerated and relatively safe. Adverse interactions between garlic supplements and several narrow therapeutic drugs, including anticoagulants (warfarin, fuindione) and HIV protease inhibitors (saquinavir, ritonavir), have been reported within the past 2 years. Animal and in vitro studies with known organosulfur constituents of garlic, as well as garlic extracts, are known to simultaneously inhibit and induce several CYP enzymes (1A, 2B, 2C, 2E and 3A subfamilies) in the liver, as well as the efflux transporter P-gylcoproptein (Pgp) in the intestinal mucosa. However, very recent studies in human subjects have produced conflicting data as to the effects of garlic supplements on cytochrome P450 function. Our specific hypotheses are: 1) the effects of garlic supplements on CYP and Pgp function vary with the type of garlic preparation (viz. garlic powder, steamed-distilled garlic oil, and aged garlic); and 2) garlic's effect is time- and regimen-dependent (e.g. it acutely inhibits and chronically induces CYP3A4 and Pgp activities in human subjects). Two separate "cocktails" of CYP and Pgp probe substrates, including caffeine (1A2), buproprion (2B6), chlorzoxazone (2E1), tolbutamide (2C9), omeprazole (2C19), metoprolol (2D6), midazolam (3A4/5), and digoxin (Pgp), will be administered to a panel of healthy human volunteers at various times during and shortly after discontinuation of daily intake of garlic supplement. Pharmacokinetics of known bioactive garlic constituents and their biotransformation products will be simultaneously studied through collection of blood, breath and urine samples. Garlic metabolite data may offer clues as to which garlic-derived compounds may be responsible for the putative metabolic effects. Specifically, we will measure metabolites deriving from allicin and allylic sulfides, which are the main constituents of garlic powder and garlic oil. We will also measure metabolites of S-allylcysteine, which is derived from hydrolysis of allylic cysteinyl peptides in garlic powder and aged garlic. These metabolic studies in human subjects will be conducted at the University of Washington General Clinical Research Center. The results will provide critical information for the design of further clinical studies to characterize and elucidate potentially important adverse garlic-drug interactions.

描述（由申请人提供）：大蒜补充剂被广泛用于治疗高血液胆固醇和脂质。直到最近，人们认为大蒜补充剂的耐受性且相对安全。在过去的两年中，已经报道了大蒜补充剂与几种狭窄的治疗药物（包括抗凝剂（Warfarin，Fuindione）和HIV蛋白酶抑制剂（Saquinavir，Ritonavir））之间的不良相互作用。已知的大蒜和大蒜提取物的动物和体外研究已知，同时抑制和诱导几种CYP酶（1A，2B，2C，2C，2E和3A亚科）在肝脏中，以及液化p-p-gylcoproptein（pgpp）（pgpp）（pgpp）。但是，关于人类受试者的最新研究产生了有关大蒜补充剂对细胞色素P450功能的影响的矛盾数据。我们的特定假设是：1）大蒜补充剂对CYP和PGP功能的影响随大蒜制剂的类型而变化（即大蒜粉，蒸蒸馏大蒜油和老化的大蒜）； 2）大蒜的作用是时间和方案依赖性（例如，它在人类受试者中急性抑制并长期诱导CYP3A4和PGP活性）。 CYP和PGP探针底物的两个单独的“鸡尾酒”，包括咖啡因（1A2），buproprion（2B6），氯唑唑酮（2E1），Tolbutamide（2C9），Omemprazole（Omeprazole（2c19），2c19），Metopolololol（2d6），Metopololol（2d6），Midopololam（2d6），simperolam（2da），daazolam（3A44/5），以及Indirand pgp p.poxin（和Ingliand da），以及Ingloxin（和Ingift）（以及Ingliand da）（以及Ingifecin（da）和Ingliand（da）和Ingliand da p。在停止每天摄入大蒜补充剂后不久和之后不久，健康的人类志愿者小组。已知生物活性大蒜成分及其生物转化产物的药代动力学将通过收集血液，呼吸和尿液样品同时研究。大蒜代谢物数据可能会提供有关哪种大蒜衍生化合物可能导致推定代谢作用的线索。具体而言，我们将测量源自大蒜素和烯丙基硫化物的代谢产物，这些代谢物是大蒜粉和大蒜油的主要成分。我们还将测量s-甲甲肌生半胱氨酸的代谢产物，该代谢物是由大蒜粉和陈年大蒜中烯丙基胱烷基肽的水解得出的。这些对人类受试者的代谢研究将在华盛顿大学一般临床研究中心进行。结果将为设计进一步的临床研究提供关键信息，以表征和阐明潜在的重要不良大蒜相互作用。